Proposal Summary DESCRIPTION (provided by applicant): Impairments in prefrontal cortical function are associated with many psychiatric disorders, including schizophrenia, mood disorders, and autism. Surprisingly, the vermis - a small part of the cerebellum best known for its role in posture and eye movements - has been strongly implicated in each of these disorders. Deficits in executive control of saccadic eye movements are used as biomarkers for schizophrenia, autism, and depression, consistent with a dual role of the vermis in regulating both motoric and prefrontal cortical function. However, neither the neural circuit substrates that link the cerebellar vermis with the prefrontal cortex nor the functional impact of these connections are understood. The central hypothesis of this proposal is that the affective and cognitive functions of the cerebellar vermis are mediated by a specific class of cerebellar nucleus neuron that makes circuit connections with the reticular activating system, a critical regulator of arousal and cortical state, as well as with neurons of the medial thalamus that are essential for prefrontal cortical function. The proposed experiments will test this hypothesis with a combination of modern anatomical, physiological, pharmacological, optogenetic, and behavioral strategies. Deficits in cerebellar engagement with the reticular activating system and the thalamus could account for mood dysregulation and cognitive deficits common to several psychiatric disorders. Accomplishing the aims of the proposed research will result in unprecedented cell type specific information about the long-range circuit connections that link the cerebellar vermis with the prefrontal cortex that account for cerebellar modulation of affective and cognitive function. This research will thus generate new insights into the mechanisms that mediate currently unexplained efficacy of transcranial stimulation of the cerebellum in improving cognitive and mood dysfunction in psychiatric disorders.